tbuckley/cabot-search huggingface dataset:
Clinical outcomes of patients with metastatic renal cell carcinoma who discontinued nivolumab +/- ipilimumab therapy electively or due to toxicity.
Authors: Jessica Heejin Yoo, Duncan Hussey, Evan Gross, Sarah P. Psutka, Scott S. Tykodi, John A. Thompson, Evan Thomas Hall
Journal: Journal of Clinical Oncology (2023)

625 Background: Immune checkpoint inhibitor (ICI) based regimens are the standard of care for patients with metastatic renal cell carcinoma (mRCC). In other tumor types such as melanoma, there is evidence that cancer control can persist long after discontinuation of ICI therapy. Outcomes after ICI discontinuation for mRCC are less characterized. Our aim is to characterize the durability of treatment response in mRCC patients who discontinued ICI therapy electively or due to toxicity. Methods: We identified patients with mRCC who responded to nivolumab +/- ipilimumab and then discontinued ICI therapy either for elective reasons or due to toxicity. Patients who discontinued therapy due to progressive disease or who died within 3 months of their last ICI dose were excluded. Complete response (CR) duration was calculated from last ICI dose to the most recent documentation of CR status. Time to progression was defined as the time from last ICI dose to documentation of disease progression or initiation of next-line therapy. Durability of treatment response was calculated from the date of last ICI dose to the most recent follow up date at which sustained response was noted. Results: We identified a total of 56 patients treated with nivolumab +/- ipilimumab therapy who discontinued treatment for toxicity (n=30) or for elective reasons (n=26) and achieved CR or partial response/stable disease (PR/SD). Of the entire cohort, 19 patients (34%) achieved CR, and the majority (95%) were still alive and disease-free with a median follow up of 906 days (range 86-2143 days). Among all patients who discontinued treatment with best response of PR/SD, 49% experienced disease progression, with a median progression-free survival of 382 days (range 77-1267). 42% of patients who stopped ICI electively achieved CR and all (100%) were still alive with sustained CR (median follow-up = 735 days) at data collection. Among those with best response of PR/SD after elective discontinuation, about half (53%) maintained disease control while the rest had disease progression or death (47%). Conclusions: Patients with mRCC who achieve CR with nivolumab +/- ipilimumab and then subsequently discontinue therapy for reasons other than disease progression have excellent long-term cancer outcomes. Recurrence and subsequent progression are rare in this group. These results are similar to the durability of ICI treatment response observed in complete responders in melanoma. Outcomes were less favorable for patients who obtained PR/SD as best response prior to ICI discontinuation, although some patients had ongoing and durable cancer control for up to several years. More research is indicated to ascertain which disease/patient features predict long-term disease control after ICI discontinuation in patients who respond favorably to ICI therapy.
Clinical and genomic factors associated with tumor mutational burden (TMB) in prostate cancer.
Authors: Helen Y Hougen, Ryon Graf, Julia C. F. C. F. Quintanilha, Gerald Li, Sanoj Punnen, Brandon A Mahal
Journal: Journal of Clinical Oncology (2023)

240 Background: TMB is an emerging biomarker to predict clinical benefit from immune checkpoint inhibitors (ICI). Although high TMB in prostate cancer is rare, and we sought to evaluate independent associations of TMB by clinical factors, prior treatment, and genomics. Methods: This study used the US-based nationwide de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites) between January 2011-March 2022. Multivariable linear regression model was used to assess independent prediction of TMB levels, which were log2+1 transformed to better normalize distribution. Data are expressed as (estimate, [95% CI], p-value). Results: The study included 2,748 tissue specimens: 51.7% were from the prostate, 10.3% from bone, and 14.6% from lymph nodes. Specimens from white patients comprised 61.2% of samples, with another 7.5% from Black, 1.1% from Asian, and 30% from other or unknown race patients. Of our cohort, 58.5%, 15.5%, and 26.0% were from patients who received 0, 1-24 months, and &gt;24 months of androgen deprivation therapy (ADT), respectively. Also 19.7%, 1.8%, 11.4%, and 0.4% had any exposure to novel hormonal therapies (NHT), Radium-223, taxanes, and ICI, respectively. Higher TMB was independently associated with ADT use &gt;24 months (0.16, [0.05-0.27], p=0.005) and Asian race (0.36, [0.03-0.69], p=0.034). Prior treatment with NHT, taxanes, or radium was not associated with higher TMB. Compared to prostate, bladder (0.22, [0.03-0.41], p=0.023), liver (0.27, [0.13-0.42], p&lt;0.001), and other (0.29, [0.15-0.43], p&lt;0.001) biopsy sites were associated with high TMB, but lymph node biopsy was not. MSI-high (2.30, [1.96-2.64], p&lt;0.001), MSI-intermediate (0.51, [0.14-0.88], p=0.007), and MSI-unknown (0.84, [0.60-1.09], p&lt;0.001) were associated with increased TMB. Individually altered genes associated with increased TMB included MLH1 (0.77, [0.31-1.24], p=0.001), MSH2 (1.09, [0.74-1.45], p&lt;0.001), MSH3 (0.64, [0.018-1.11], p=0.006), MSH6 (0.94, [0.61-1.26], p&lt;0.001), BRCA2 (0.56, [0.43-0.69], p&lt;0.001), CDK12 (0.38, [0.24-0.53], p&lt;0.001), FANCA (0.42, [0.07-0.77], p=0.02), MRE11 (0.87, [0.11-1.62], p=0.025), and PALB2 (0.83, [0.48-1.18], p&lt;0.001). No individual gene was independently associated with lower TMB. Conclusions: TMB associates with MSI status and MMR genes. However, aside from associating with long term ADT use, TMB does not have strong association with prior systemic treatment. Certain biopsy specimen sites including bladder and liver have increased TMB but overall, the association is relatively weak in comparison to MMR genes and MSI status. This study allows better understanding of how prior treatments, clinical and genomic factors affect TMB status, which may add value to MSI status in predicting treatment response in advanced prostate cancer.
POMB/ACE, a cocktail of 7 drugs to treat intermediate to poor prognosis and high volume germ cell cancers: A large retrospective study.
Authors: Sarah Howlett, India Reid, Andrew Gogbashian, Rebecca Devine, Linda Charalambous, Samita Agarwal, Anand Sharma
Journal: Journal of Clinical Oncology (2023)

419 Background: Patients presenting with intermediate and poor risk germ cell tumours tend to be young and fit. Although more than half of patients may hope to be cured, a proportion will die because of their cancer. An aggressive strategy is required to maximise the chance of cure. Alternating high dose chemotherapy regimens have been trialled with varying outcomes. We present real world data demonstrating the efficacy and safety of first-line POMB/ACE (Cisplatin, Vincristine, Methotrexate, Bleomycin alternating with Actinomycin D, Cyclophosphamide, Etoposide) for these patients. Methods: 40 metastatic germ cell patients treated with POMB/ACE were identified at our centre. Patients were classified as being in intermediate or poor prognostic groups based on the International germ cell cancer collaborative group classification (IGCCCG). Treatment was administered every 2 weeks for up to 7 cycles. Response to treatment was determined by radiological imaging and serum tumour markers. Toxicities were evaluated using CTCAE version 5.0. Results: Clinical characteristics were as follows: median age at diagnosis 32 years (range 18-69). 36 patients (90%) were male and 4 patients (10%) were female. 29 (73%) presented with poor risk disease and 11 (27%) with intermediate risk. Patients completed between 1 and 7 cycles of POMB/ACE with the median number of cycles being 5. Data on toxicity severity was collected where available. This is summarised in the table. One grade 4 event was noted. 10 patients experienced grade 3 toxicities. Interestingly no patients were reported to develop bleomycin lung toxicity. This may be due to bleomycin being omitted in patients felt to be at higher risk of lung toxicity (smokers, older patients, pre-existing lung conditions). 30 (75%) patients were progression free following POMB/ACE. 9 (22%) patients went on to have subsequent systemic chemotherapy regimens and high dose stem cell transplant (HDSCT), as they had high volume disease, and persistent marker positive disease. 16 (40%) patients went on to have further surgical interventions, most commonly retroperitoneal lymph node dissection (RPLND), no active malignancy was seen in the resected specimen. At a median follow-up of 43 months, 39 (97.5%) of patients are still alive. Conclusions: POMB/ACE is a safe and effective regimen for patients presenting with intermediate to poor risk germ cell tumours. Patients with high volume disease should be considered for subsequent HDSCT to achieve better outcomes. [Table: see text]
Survey of keratin 17 (K17) expression in different urothelial malignancies.
Authors: Thorsten Ecke, Ralph M. Wirtz, Gregor Barth, Stefan Koch, Sholeh Jahanfard, Nam W Kim
Journal: Journal of Clinical Oncology (2023)

458 Background: The current non-invasive urine tests tend to display low sensitivity for the detection of urothelial cancers, especially in low-grade cancer. Recent reports suggest that the URO17 test based on the Keratin 17 (K17) biomarker displays high sensitivity and specificity in the detection of urothelial carcinoma in both low-grade and high-grade cancers and show promise as an effective non-invasive test for bladder cancer. The current study aimed to evaluate K17 expression in different histological categories of urological diseases. Methods: Ninety-five urine specimens were collected from 2020-2021 that represented 19 different histological categories of urothelial diseases. These samples were prepared onto slides and tested with the URO17 Bladder Cancer test (KDx Diagnostics Inc.) on DAKO Link48 autostainer using the manufacturer’s recommended procedures. The stained samples were evaluated by a cytopathologist and scored using five K17-positive urothelial cells as a cut-off. Results: K17 was positive in 20/20 (100%) of the urothelial carcinoma, and 23/27 (85%) of Non-invasive papilloma and urothelial carcinomas. K17 was positive in 100% of carcinoma in situ, papillary urothelial carcinoma, sarcoma, and small cell carcinoma, papillary urothelial carcinoma, urothelial papilloma, inverted papilloma, renal-pelvis urothelial carcinoma, and urothelial carcinoma with squamous differentiation. K17 was also expressed in many cystitis, inflammatory myofibroblastic tumors, and PUNLMP, but not in prostate carcinoma. In 19/22 cases (86%) K17 was mostly positive in urine samples from patients with prior history of bladder cancer, but were histologically determined to be benign. The overall sensitivity of K17 in the cancer group was 88.5% (54/61 positive) with K17 being expressed in both high-grade and low-grade cancers. Of the seven false-negative samples, five were low-grade, one was high-grade, and one was from the inflammatory myofibroblastic tumor. Conclusions: Keratin 17 is highly expressed in almost all cases of urothelial carcinoma including those of papillary and squamous characteristics, confirming the high sensitivity of K17 in detecting all categories of urothelial carcinoma. Keratin 17 was also observed in many benign and premalignant conditions such as cystitis, PUNLMP, and metaplasia suggesting the K17 expression can result from a trauma to urothelium that could lead to activation of K17 in regenerating urothelial cells. Additional studies are ongoing to confirm and expand the utility of the K17 biomarker in bladder cancer.
Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (NEO-GDFATHER).
Authors: Andrea Necchi, Roberto Iacovelli, Massimo Di Maio, Paolo Gontero, Petra Fettes, Kathrin Klar, Frank Hermann, Eugen Leo
Journal: Journal of Clinical Oncology (2023)

TPS595 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Recently, neoadjuvant immunotherapy (I/O) has demonstrated clinical safety and efficacy in various solid tumor indications including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for successful treatment of MIBC in the future. Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts have indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that has demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. This clinical trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: This is a multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. No statistical assumptions have been undertaken at this stage. Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations according to EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., Annals of Oncology (2022) 33 (suppl_7): S331-S355.
Access to care and health care quality metrics in urban versus rural patients (pts) with advanced prostate cancer (aPC).
Authors: Haoran Li, Kamal Kant Kant Sahu, Shruti Adidam Kumar, Vinay Mathew Thomas, Nishita Tripathi, Georges Gebrael, Nicolas Sayegh, Beverly Chigarira, Yeonjung Jo, Umang Swami, Sumati Gupta, Benjamin L. Maughan, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

37 Background: Compared to the urban population, pts in rural areas face healthcare disparities and experience inferior healthcare-related outcomes. Herein we aimed to compare the health care quality metrics and outcomes between pts with aPC from rural versus urban areas treated at a tertiary cancer hospital. Methods: In this IRB approved retrospective study, eligibility criteria were: presence of aPC, treatment at a single center (NCI-Designated Comprehensive Cancer Center (NCI-CCC), between 10/2017 to 9/2021). Rural-urban commuting area (RUCA) codes from the 2010 census /were used to classify the pts’ residences as urban (1-3) or rural (4-10) areas. The straight-line to distance of the pts’ place of residence from our institute was also calculated and included in the analysis. The median household income data were obtained and calculated from “The Michigan Population Studies Center”, based on individual zip codes. Results: A total of 994 pts were eligible and included (83.9% urban vs 16.1% rural). The baseline demographic profile and tumor characteristics were similar between the two groups. The median household income of pts from urban areas was higher by $8604/annum than that from rural areas (p&lt;0.0001). There was no difference between urban versus rural pts in terms of receipt of lines of systemic therapies, clinical trial accrual, and receipt of tumor genomic profiling. No significant difference was found in the median overall survival between the two population (83.7 versus 92.8 months; p=0.14). Conclusions: These hypothesis generating data show that access to quality care, as available in an NCI-CCC can mitigate the disparities in the quality of health care delivery and clinical outcomes in urban versus rural pts with aPC. [Table: see text]
Spatial immunophenotypes of distant metastases and response to immune checkpoint inhibition.
Authors: Franziska Erlmeier, Niklas Klümper, Pamela Strissel, Reiner Strick, Danijel Sikic, Veronika Bahlinger, Johannes Breyer, Manuel Ritter, Christian Bolenz, Florian Roghmann, Philipp Erben, Kristina Schwamborn, Ralph M. Wirtz, Thomas Horn, Bernd Wullich, Michael Hölzel, Arndt Hartmann, Jürgen E. Gschwend, Wilko Weichert, Markus Eckstein
Journal: Journal of Clinical Oncology (2023)

538 Background: The value of PD-L1 to predict durable responses to immune checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue. Objective: To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes and MHC-I determined in patient-matched PRIM/MET. Methods: PD-L1 (Ventana IC-Score, combined positivity score), spatial immunephenotypes (midi-plex digital spatial immuneprofiling) and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs). 119 patients received first-line platinum-based chemotherapy, and 50 patients received second-line immunecheckpoint inhibition. PD-L1 expression, spatial immunephenotypes and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated to chemotherapy and ICI response and outcomes. Results: Discordance rates in patient-matched PRIM/MET amounted 25/30%, 36% and 49% for PD-L1 (CPS10/IC5%), immunephenotypes and MHC-I (loss versus preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICI, patients with cytotoxic tumor immune microenvironments (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95%-CI:0.01-0.65) versus patients with immunedepleted MET (DCR 29%). MET MHC-I status added incremental value to predict durable ICI responses: Combination of MHC-I based (auto-)antigen expression of tumor cells with spatial immunepehnotypes in pre-treatment MET improved predictive and prognostic impact for response and outcome prediction of mUC patients undergoing first-line platinum-based chemotherapy and second-line immunecheckpoint inhibition. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level. Conclusions: The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pre-treatment MET-biopsies reflecting the current immunological disease state than on PRIM.
Oncologic outcomes in patients with residual invasive upper tract urothelial carcinoma following neoadjuvant chemotherapy.
Authors: Sean A. Fletcher, Maximilian Pallauf, Emelia K. Watts, Kara A. Lombardo, Jack A. Campbell, Andrea Mari, Morgan Rouprêt, Stephen A. Boorjian, Hooman Djaladat, Eiji Kikuchi, Francesco Soria, Michael Rink, Jay D. Raman, Firas Abdollah, Guillaume Ploussard, Jean H. Hoffman-Censits, David James McConkey, Shahrokh F. Shariat, Benjamin Pradere, Nirmish Singla
Journal: Journal of Clinical Oncology (2023)

475 Background: Emerging evidence supports use of neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for appropriately selected patients with upper tract urothelial carcinoma (UTUC). However, oncologic outcomes have not been well characterized for patients with residual muscle-invasive disease after NAC. Methods: We used a multi-institutional cohort from 24 centers in the U.S., Europe, and Japan to retrospectively identify patients who underwent RNU for UTUC from 1985-2022 and had high-grade muscle-invasive disease. We stratified the cohort based on receipt of NAC (&gt;ypT2 vs. &gt;pT2). Exclusion criteria included receipt of adjuvant chemotherapy, concurrent cystectomy with RNU, and distant metastatic disease. Baseline characteristics were compared between groups. Kaplan-Meier survival analysis with log-rank test was used to compare differences in recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Multivariable Cox regression and Fine-Gray competing risk regression were used to determine predictors of these outcomes. Results: A total of 1,233 patients were included, 62 of whom received NAC prior to RNU. A platinum-based regimen was used in 90% of NAC recipients, and the median number of cycles administered was 4 (IQR: 3-5). Median follow-up time among all patients was 22 months (IQR: 8-47 mo.). NAC recipients were more likely to have pathologic node positivity (35% vs. 13%) and less likely to have positive tumor margins (8% vs. 28%). On Kaplan-Meier analysis, NAC recipients with residual &gt;ypT2 disease had poorer outcomes than those with &gt;pT2 disease (2-year RFS [NAC vs. no NAC]: 52% vs. 80%, p&lt;0.001; 2-year OS: 60% vs. 78%, p=0.003; 2-year CSS: 61% vs. 86%, p&lt;0.001). Multivariable analyses also showed a statistically significant association between residual muscle-invasive disease after NAC and poorer RFS, OS, and CSS (Table). Conclusions: NAC recipients with &gt;ypT2 disease at RNU after exhibit poorer outcomes than stage-matched chemotherapy naïve counterparts. This may reflect effects of occult micrometastatic disease or chemoresistant primary tumors in non-responders. Our data highlight the need to improve prospective identification of candidates most likely to respond to NAC prior to RNU for UTUC in order to maximize its therapeutic benefit. [Table: see text]